1
Authors
Arbey Aristizabal-Alzate1
John Fredy Nieto-Rios1,2 Catalina Ocampo-Kohn1,2 Lina Maria Serna-Higuita3 Diana Carolina Bello-Marquez2 Gustavo Adolfo Zuluaga-Valencia1
1Hospital Pablo Tobón Uribe, Me-dellín, Antioquia, Colombia. 2Universidad de Antioquia, Medellín, Antioquia, Colombia.
3University of Tüebingen, Tübingen, Germany.
Submitted on: 04/24/2018. Approved on: 07/30/2018.
Correspondence to: Lina Maria Serna-Higuita. E-mail: lm.serna@hotmail.com
Successful multiple-exchange peritoneal dialysis in a patient
with severe hematological toxicity by methotrexate: case
re-port and literature review
Diálise peritoneal com múltiplas trocas bem-sucedida em paciente
com grave toxicidade hematológica por metotrexato: relato de caso
e revisão de literatura
Apesar de sua toxicidade, o metotrexato é um medicamento eficaz no controle de várias doenças. A mielossupressão, um de seus principais efeitos adversos, aumenta em gravidade e frequência nos pacientes com in-suficiência renal. Apresentamos o caso de um homem de 68 anos de idade com doença re-nal termire-nal relacionada à vasculite associada ao ANCA em diálise peritoneal, que recebeu a medicação em dose baixa em função da atividade da doença e que teve como com-plicação pancitopenia grave com mucosite, tratada com medidas de suporte e diálise peritoneal com múltiplas trocas. Revisamos 20 casos publicados até o presente momento sobre pancitopenia associada a metotrexato em pacientes em diálise. Foi identificada alta morbidade e mortalidade, razão pela qual seu uso nesse tipo de paciente não é reco-mendado. No entanto, quando esta compli-cação ocorre, uma opção terapêutica pode ser o uso de diálise peritoneal com múltip-las trocas, além da terapia de suporte para toxicidade medicamentosa. Maiores estudos são necessários para demonstrar o papel da diálise peritoneal com múltiplas trocas na re-moção desse medicamento.
R
ESUMOPalavras-chave: Metotrexato; Pancitopenia; Insuficiência Renal; Diálise Peritoneal.
Methotrexate is an effective medication to control several diseases; however, it can be very toxic, being myelosuppression one of its main adverse effects, which increases in severity and frequency in patients with renal failure. We present the case of a 68-year-old man with chronic, end-stage renal disease as-sociated with ANCA vasculitis, under treat-ment with peritoneal dialysis, who received the medication at a low dose, indicated by disease activity, which presented as a com-plication with severe pancytopenia with mu-cositis that improved with support measures and multiple-exchange peritoneal dialysis. We reviewed 20 cases published to date of pancytopenia associated with methotrexate in patients on dialysis and found high mor-bidity and mortality, which is why its use in this type of patient is not recommended. However, when this complication occurs, a therapeutic option could be the use of mul-tiple-exchange peritoneal dialysis in addition to supportive therapy for drug-related toxici-ty, although it is recognized that studies are required to show the role of multiple-exchan-ge peritoneal dialysis in the removal of this medication.
A
BSTRACTKeywords: Methotrexate; Pancytopenia; Renal Insufficiency; Peritoneal Dialysis.
DOI: 10.1590/2175-8239-JBN-2018-0095
INTRODUCTION
Methotrexate is a disease-modifying, anti-rheumatic drug, used in treatment schemes for different diseases; however, its long-term use can cause adverse effects in up to 61% of patients, causing the dis-continuation of medication in 20%1. One of the most feared complications due to its high morbidity and mortality is mye-losuppression;2,3 impaired renal function, advanced age, diabetes mellitus, folic acid
deficiency, and hypoalbuminemia are the main risk factors for developing the complication.4
are not specific regarding the safety of adminis-tering methotrexate in the presence of established ESRD and/or dialysis, and its use at low doses in these patients is still controversial. This gap may result in the false belief that its administration is safe in such circumstances; in addition, some au-thors have interpreted that bone marrow depres-sion caused by methotrexate as an idiosyncratic effect.6 However, there are reports of patients with ESRD who after receiving methotrexate therapy, even at low doses, presented severe complications, and currently there is no clarity about which is the best dialysis therapy to eliminate this toxic substance.
Next, we report the case of a patient diagnosed with ESRD on treatment with peritoneal dialysis who was treated with methotrexate for a diagnosis of granulomatosis with polyangiitis (Wegener). A few days after starting the medication, the patient developed a severe pancytopenia, which was succes-sfully handled with support therapy and intensive peritoneal dialysis.
CASE REPORT
A 68-year-old man presented with a diagnosis of granulomatosis with polyangiitis that evolved for 6 years with paranasal, ocular, pulmonary, and renal involvement. As a consequence of ESRD, the patient required automated peritoneal dialy-sis for the last 3 years. For relapse of vasculitis, he received 7.5 mg methotrexate weekly. After the second dose, he presented odynophagia, asthenia, adynamia, melenic depositions, bleeding from the gums, oral ulcers, and painful lesions on the skin of his lower limbs. On admission, it was found a sleepy, febrile patient, with blood pressure 99/57 mmHg, heart rate of 97 per minute, and respira-tory rate of 17 per minute. Clinical findings in-cluded necrotic lesions on the lower lip, ulcers on the cheeks, aphthae on the tongue, and macu-les with erythematous edges on his inner thighs. Laboratory tests showed high levels of inflamma-tory reactants, pancytopenia, and elevated levels of methotrexate (table 1). With the above, it was established a diagnosis of methotrexate toxicity
Study Laboratory values at admission Laboratory values at discharge
BUN 78 mg/dL
C-Reactive protein 22.78 mg/dL
Erythrosedimentation 120 mm/hour
Hemogram
Hemoglobin: 8.6 g/dL, Leukocytes 1300 x mm3, Neutrophils: 14 %,
Lymphocytes: 63%, eosinophils: 11%, Platelets: 26,000 x mm3
Hemoglobin 7.7 g/dL Leukocytes 13,300 x mm3, Neutrophils 70 %,
Lymphocytes 19%, Platelets 222,000 x mm3.
Ionogram Na: 138 mmol/L, Cl 96 mmol/L, K 3.6
mmol/L, Ca 7 mg/dL.
Blood cultures Negative
Gram and sputum culture Negative
Urine culture Negative
Methotrexate levels 0.5 micromoles/L Undetectable
Chest x-ray: Basal bilateral mixed pulmonary
infiltrates.
Computerized Axial Tomography of the chest
Alveolar opacities in the lower lobes and posterior segment of the right
upper lobe.
Braz. J. Nephrol. (J. Bras. Nefrol.) 2018, Ahead of Print
Successful treatment with peritoneal dialysis in a patient with hematological toxicity by methotrexate
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with hematological compromise, as well as of skin and mucous membranes lesions; and as a conse-quence, febrile neutropenia with septic shock was diagnosed. Management was started in the inten-sive care unit with piperacillin, tazobactam, van-comycin, fluconazole, steroids in stress doses, su-pport with norepinephrine, calcium folinate, and granulocyte colony stimulating factor. He was also managed with multiple-exchange peritoneal dialysis 20 hours a day (2 periods of 10 hours, 11 liters per period distributed in 6 liters x 2.5% and 5 liters x 1.5%, 10 cycles in total) in order to in-crease the clearance of the methotrexate and avoid the installation of a hemodialysis catheter in a pa-tient with severe thrombocytopenia. All the cultu-res taken were negative, so antibiotics were sus-pended after 5 days. The patient evolved towards improvement and within a week, his hematologi-cal cell count recovered, fever did not return, and he recovered from his skin and mucosal lesions; in addition, a new measurement of methotrexate showed no detectable levels.
DISCUSSION
Methotrexate (molecular weight 454.4 kDa) is an antimetabolite of folic acid that inhibits dihydrofola-te reductase, a key enzyme for the production of dihydrofola- te-trahydrofolates, which are required for the synthesis of purines and pyrimidines, and therefore, it inhibits the cell cycle.7
The pharmacokinetics of methotrexate is hi-ghly variable and unpredictable.8 It is rapidly ab-sorbed after oral administration, reaching serum levels after one hour, with a binding to albumin of 50%. It is distributed in extravascular compart-ments, including kidneys, liver, and synovial fluid. Within the cells, it is converted to methotrexate polyglutamates, which are more potent increasing its intracellular half-life. It is partially oxidized in the liver to 7-hydroxy-methotrexate, a less ac-tive metabolite, and it is excreted mainly by the kidneys, and in lesser amount by the liver. More than 90% of the absorbed amount is excreted in the urine at 48 hours by glomerular filtration and active tubular secretion. The elimination half-life is 5 to 8 hours, but it increases significantly when there is acute or chronic renal failure, especially in advanced stages, which leads to a reduction in the
clearance of methotrexate and an increase in its toxicity.9 At present, there are no pharmacokinetic parameters that correlate with efficacy, and plas-ma concentration cannot predict clinical response or adverse effects.10
Methotrexate is widely used in cancer, rheu-matological diseases, inflammatory bowel disease, and obstetric conditions. In patients with rheu-matoid arthritis and normal renal function, the recommended dose is between 5 and 7.5 mg we-ek, with a maximum dose of 15 mg week.11 This drug mainly affects the cells of fast division, a re-ason why it has deeper action on the cells of the bone marrow and the gastrointestinal tract. The destruction of bone marrow cells predisposes the patient to thrombocytopenia, granulocytopenia, and lymphopenia, which can lead to life-threate-ning infections, severe anemia and gastrointestinal tract hemorrhage. Other additional adverse effects are nausea, vomiting, stomatitis, and pulmonary and hepatic toxicity.
Toxicity associated with the use of methotrexa-te has been repormethotrexa-ted even in therapeutic doses and in patients who don’t need renal replacement the-rapy. Gutierrez-Ureña and colleagues identified 70 dialysis-free patients who presented pancytopenia related to methotrexate, with a mortality rate of 17.1%.4 Lim and colleagues identified 25 cases in a period of 5 years, with an average age of 76 years, a dose of 12.5 mg week, a therapeutic duration of 36 months, 40% with a leukocyte count less than 2000/mm³, 30% (8 out of 25) of the patients had renal failure, and the mortality rate was 28%.3 In the presence of advanced renal failure and in pa-tients on dialysis, the risk of toxicity is greater, even at low doses, with presence of higher plasma levels and longer half-lives (even detectable up to 3 weeks after receiving small doses of 2.5 mg).
Braz. J. Nephrol. (J. Bras. Nefrol.) 2018, Ahead of Print
Successful treatment with peritoneal dialy
sis in a patient with hematological to
xicit
y b
y methotre
xate
Reference Sex Age Type of dialysis Indication Dose (mg/week)
Duration (weeks)
Cumulative Dose (mg)
Level of methotrexate
( mol/L) Nadir leukocytes Result
Diskin (12) M 60 PD RA 10 2 20 0.53 300 Dead
Chess (13) M 64 PD Psoriasis - - 35 - 300 Dead
Sun (14) F 33 PD Lupus Arthritis 5.0 2 25 - 600 Recovered
Liu WC (15) F 61 PD Eczema 7.5 3 22.5 0.08 30 Recovered
Elman (16) F 52 HD RA 2.5 Single dose 2.5 0.13 500 Dead
Elman (16) F 47 HD Systemic
sclerosis 2.5 Single dose 2.5 - 1500 Recovered
Nakamura (17) M 57 HD RA 5.0 Single dose 5.0 0.03 100 Recovered
Chatham (18) M 49 HD Myositis - 2 - - 90 Recovered
Chatham (18) M 52 HD Myositis 5.0 Single dose 5.0 - 2200 Recovered
Chatham (19) F 61 HD Psoriasis 2.5 3 7.5 - 50 Dead
Boulanger (11) F 60 HD RA 5.0 2 10.0 - 1300 Recovered
Basile (19) (20) F 74 HD RA 5.0 2 10.0 - 1700 Recovered
Boey (9) M 66 HD Psoriasis 5.0 2 10.0 0.03 70 Recovered
Yang (20) F 55 HD RA 7.5 12 90.0 0.11 400 Dead
Seneschal (21) M 76 HD PB 5.0 1.5 7.5 0.47 550 Dead
Cheung (22) M 56 HD Psoriasis 2.5 Single dose 2.5 0.06 60 Dead
Liu H. (23) M 48 HD PB 10 2 20 0.14 1800 Recovered
Mima (24) M 46 HD RA - - - - 690 Recovered
Flynn (25) M 68 PD CA squamous
cells 2.5 intra-lesion Single dose 25 0.03 600 Recovered
Current report M 68 PD vasculitis 7.5 2 15 0.005 600 Recovered
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Successful treatment with peritoneal dialysis in a patient with hematological toxicity by methotrexate
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When analyzing these 20 patients, average age of 57.6 years, it is found that they received a cumulative dose of 17.5 mg. The average dose was 5.2 mg/we-ek, for an average therapeutic duration of 2 weeks. Nineteen of the 20 patients had nadir leukocytes less than 2000/mm³, which is defined as severe leukope-nia. The mortality rate was 35% (7 of 20). Comparing patients who received methotrexate without dialysis with patients on dialysis, it was found that dialysis patients were relatively younger, had a short duration of dose, low cumulative dose, and severe leukope-nia compared to patients who were not on dialysis. Mortality was also higher in dialysis patients. In ge-neral, the patients who died had a lower nadir of leu-kocytes and higher levels of methotrexate than those who recovered. In any case, the final result depends on several factors, such as comorbidities, cumulati-ve dose, methotrexate clearance, early detection and medical care.
In the case reported here, the patient was on pe-ritoneal dialysis and a low dose of methotrexate was used according to the indication for rheumatological pathology. As he presented a complication of severe pancytopenia and mucositis, he was possibly more susceptible to presenting toxicity for this drug.
The efficacy of methotrexate removal by dialysis has been associated with the toxicity of methotre-xate. There are reports of methotrexate removal by hemodialysis and hemoperfusion, with both methods effectively removing the drug thanks to its binding to proteins by 50%. However, there is a post-dialysis re-bound in the methotrexate concentration of 90-100% to the levels prior to the procedure; therefore, patients may require daily or continuous renal replacement therapy to avoid rebound toxicity.25 However, little is known about removal by peritoneal dialysis.
Ahmad and colleagues26 reported a case of acu-te kidney injury caused by methotrexaacu-te, in which emergency acute peritoneal dialysis was performed for 7 days, using 34 to 40 L/day of dialysate without finding a change in the serum concentration of this drug; however, the number or frequency of exchan-ges or volumes of permanence were not reported. Diskin and colleagues12 reported that clearance of methotrexate in peritoneal dialysis was less effective than in hemodialysis; they performed an exchange of peritoneal dialysis (3 L volume for 6 hours) follo-wed by high flow hemodialysis for 7 hours. After the 6-hour peritoneal dialysis exchange, the methotrexate
concentration only decreased from 0.53 to 0.47 micromoles/liter. They also showed that the remo-val of methotrexate by means of peritoneal dialysis was mainly in the first hour of exchange. However, Murashima and colleagues27 reported the case of a patient on peritoneal dialysis treated with a high dose of methotrexate for lymphoma in the central nervous system. For the initial cycles of methotrexate, he re-ceived temporary high-flux daily hemodialysis, star-ting 24 hours after the infusion of methotrexate to avoid toxicity; but later, due to problems with vascu-lar access, he was treated with continuous peritoneal dialysis of multiple exchanges for the last 2 cycles of chemotherapy (the intensive peritoneal dialysis con-sisted of 20 cycles in 24 hours, with residence times of 30 minutes, 1.8 liters of fluid admitted). The clearan-ce for high flow hemodialysis was 0.77 mL/kg/min; and for peritoneal dialysis, 0.65 mL/kg/min. Despite a lower clearance for peritoneal dialysis, the patient did not develop clinical evidence of methotrexate toxicity.
In our case, the use of multiple-exchange perito-neal dialysis was chosen to avoid the installation of a hemodialysis catheter due to thrombocytopenia. It was adjusted to the automated peritoneal dialysis prescription that the patient received previously; basi-cally, the night cycle of automated peritoneal dialysis was repeated during the day, thus increasing the volu-me of peritoneal dialysis from 11 liters to 22 liters. A new measurement of methotrexate showed no detec-table levels, the patient recovered the leukocyte count, and survived; therefore, we propose that an option for the treatment of methotrexate-associated toxicity in patients on peritoneal dialysis could be multiple--exchange peritoneal dialysis without having to trans-fer the patient to hemodialysis; in our case, this was easily accomplished by modifying the usual peritoneal dialysis of the patient. However, more studies are re-quired to confirm if such dialysis method can prevent and correct the toxicity associated with methotrexate.
CONCLUSION
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